DE3534421A1 - USE OF THIENYLAMINES AS PERFORMANCE AGENTS, NEW THIENYLAMINE - Google Patents

Description

The present invention relates to the use of partially known substituted thienylamines as performance enhancing agents in animals.

Thienylamines have already become known. you find Use as a crop protection agent, intermediate products for Dye production and pharmaceuticals (cf. DE-OS 21 22 636, EP-OS 4 931, US-P 43 17 915, 44 47 624).

However, there is nothing about their use as performance enhancing Means become known in animals.

1. It has been found that substituted thienylamines of the formula I in which
A stands for the rest Ia X represents O or S,
R ^{1 represents} hydrogen, halogen, nitro, CN, alkoxy, alkylthio, haloalkoxy, haloalkylthio, optionally substituted radicals from the group alkyl, acyl, aroyl, aryl,
R ^{2 represents} hydrogen, halogen, nitro, CN, alkoxy, alkylthio, haloalkoxy, haloalkylthio, optionally substituted radicals from the group acyl, aroyl, alkyl, aryl,
R ¹ and R ² together with the adjacent C atoms represent an optionally substituted saturated or unsaturated carbocyclic or heterocyclic ring which can optionally carry a carbonyl function,
R ^{3 represents} the residues CN, COR ⁶ , COOR ⁷ , CONR ⁸ R ⁹ ,
R ^{4 represents} hydrogen or alkyl,
R ^{5 represents} optionally substituted alkyl, cycloalkyl, alkenyl, optionally substituted aryl,
R ^{6 represents} optionally substituted alkyl or optionally substituted aryl,
R ^{7 represents} hydrogen, optionally substituted alkyl, cycloalkyl, alkenyl, optionally substituted aryl,
R ^{8 represents} alkyl or cycloalkyl,
R ^{9 represents} optionally substituted alkyl,
have excellent performance-enhancing effects in animals.

The substituted thienylamines of formula I are partially known. As far as they are new, they can can be produced by methods known per se.

2-aminomethoxycarbonyl-3-carboethoxy-4-ethyl-5-methyl thiopen is new.

It was completely surprising that the substituted thienylamines Formula I performance-enhancing properties in animals. There was from the state of the art no reference to this new use of the partial known substituted thienylamines of the formula I.

Substituted thienylamines of the formula I in which are preferred
A stands for the rest Ia,
X represents O or S,
R ¹ for hydrogen, halogen, nitro, CN, C _1-4 alkoxy, C _1-4 alkylthio, optionally substituted C _1-6 acyl, optionally substituted aroyl, in particular benzoyl, for optionally by halogen, C _1-4 -Alkoxy, C _1-4 -alkylthio, aryl, in particular phenyl, aryloxy, in particular phenoxy, arylthio, in particular phenylthio, amino, C _1-4 -alkylamino, di-C _1-4 -alkylamino, arylamino, in particular phenylamino substituted C _{1 -6-} alkyl and phenyl, the phenyl radicals optionally bearing one or more of the following substituents: halogen, C _1-4 -alkyl, CN, C _1-4 -alkoxy, C _1-4 -alkylthio, phenyl, phenoxy, phenylthio, amino, C _1-4 alkylamino, di-C _1-4 alkylamino, C _1-4 alkoxyalkyl, C _1-4 - haloalkyl, C _1-4 haloalkoxy, C _1-4 haloalkylthio, methylenedioxy or Ethylenedioxy, which are optionally halogen-substituted, acyl,
R ^{2 represents} the radicals listed for R ¹ .
R ¹ and R ² together with the adjacent two C atoms represent saturated or unsaturated carbocyclic radicals with 5-8 ring members, which are optionally substituted by OH, C _1-4 alkyl, halogen, nitro, CN, C _1-4 alkoxy , C _1-4 alkylthio, phenyl, phenoxy, phenylthio, amino, C _1-4 alkylamino, C _1-4 dialkylamino, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _1-4 haloalkylthio , C _1-4 alkoxyalkyl are substituted and one of the ring members which are not bonded to the thiophene ring can carry a carbonyl function (C = O); in the event that R ¹ and R ² form a heterocyclic ring with the adjacent C atoms, this has 5-6 ring members and carries O, S or N as heteroatoms.
R ^{3 represents} the rest CN, COR ⁶ , COOR ⁷ , CONR ⁸ R ⁹ ,
R ^{4 represents} hydrogen or C _1-4 alkyl,
R ⁵ for optionally by halogen, C _1-4 alkoxy, C _1-4 alkylthio, aryl, in particular phenyl, aryloxy, in particular phenoxy, arylthio, in particular phenylthio, amino, C _1-4 alkylamino, di-C _{1- 4-} alkylamino substituted C _1-6 -alkyl, C _3-8 -cycloalkyl, C _2-6 -alkenyl furthermore represents phenyl or naphthyl, where the phenyl radicals optionally carry one or more of the following substituents: halogen, C _1-4 - Alkyl, CN, C _1-4 alkoxy, C _1-4 alkylthio, phenyl, phenoxy, phenylthio, amino, C _1-4 alkylamino, di-C _1-4 alkylamino, C _1-4 alkoxyalkyl, C _1-4 -haloalkyl, C _1-4 -haloalkoxy, C _1-4 -haloalkylthio, methylenedioxy or ethylenedioxy, which are optionally halogen-substituted,
R ⁶ for optionally by halogen, C _1-4 alkoxy, C _1-4 alkylthio, aryl, in particular phenyl, aryloxy, in particular phenoxy, arylthio, in particular phenylthio, amino, C _1-4 alkylamino, di-C _{1- 4-} alkylamino substituted C _1-6 alkyl, furthermore represents phenyl or naphthyl, where the phenyl radicals optionally carry one or more of the following substituents: halogen, C _1-4 alkyl, CN, C _1-4 alkoxy, C _{1 -4} alkylthio, phenyl, phenoxy, phenylthio, amino, C _1-4 alkylamino, di-C _1-4 alkylamino, C _1-4 alkoxyalkyl, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _1-4 haloalkylthio, methylenedioxy or ethylenedioxy, which are optionally halogen-substituted,
R ⁷ for optionally by halogen, C _1-4 alkoxy, C _1-4 alkylthio, aryl, in particular phenyl, aryloxy, in particular phenoxy, arylthio, in particular phenylthio, amino, C _1-4 alkylamino, di-C _{1- 4-} alkylamino substituted C _1-6 -alkyl, C _3-8 -cycloalkyl, C _2-6 -alkenyl furthermore represents phenyl or naphthyl, where the phenyl radicals optionally carry one or more of the following substituents: halogen, C _1-4 - Alkyl, CN, C _1-4 alkoxy, C _1-4 alkylthio, phenyl, phenoxy, phenylthio, amino, C _1-4 alkylamino, di-C _1-4 alkylamino, C _1-4 alkoxyalkyl, C _1-4 -haloalkyl, C _1-4 -haloalkoxy, C _1-4 -haloalkylthio, methylenedioxy or ethylenedioxy, which are optionally halogen-substituted,
R ^{8 represents} C _1-4 alkyl, C _3-8 cycloalkyl,
R ^{9 represents} C _1-4 alkyl.

Compounds of the formula I in which
A represents the rest Ia in the 2-position of the thiophene ring,
X stands for O,
R ^{1 is} hydrogen, C _1-6 alkyl which is optionally substituted by fluorine, chlorine or bromine, phenyl which is optionally substituted by C _1-4 alkyl, halogen, C _1-4 haloalkyl, in particular trifluoromethyl, C _{1- 4} haloalkoxy, in particular trifluoromethoxy, is nitro, acyl, in particular acetyl,
R ^{2 represents} the radicals specified for R ¹ ,
R ¹ and R ² together represent - (CH ₂ ) _3-6 -
R ³ in the 3-position of the thiophene ring represents the residues CN, COR ⁶ , COOR ⁷ , CONR ⁸ R ⁹ ,
R ^{4 represents} hydrogen,
R ^{5 is} C _1-6 alkyl, C _1-4 alkylthio-C _1-4 alkyl, cycloalkyl with up to 8 C atoms, C _2-4 alkenyl, phenyl, which is optionally replaced by C _1-4 - Alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, halogen, in particular chlorine, nitro, is substituted, or naphthyl,
R ^{6 represents} C _1-4 alkyl, in particular methyl and ethyl,
R ^{7 represents} C _1-4 alkyl, in particular methyl, ethyl, n-, i-propyl, n-, t-butyl, C _2-4 alkenyl, in particular alkyl, and also phenyl,
R ^{8 represents} C _1-4 alkyl,
R ^{9 represents} C _1-4 alkyl, especially methyl, ethyl.

Compounds of the formula I, in which
A in the 2-position of the thiophene ring represents the rest of the formula Ia,
R ^{1 represents} hydrogen, C _1-5 -alkyl, in particular methyl, ethyl, isopropyl, t-butyl, n-pentyl, acetyl, phenyl, nitro,
R ^{2 represents} the radicals listed for R ¹ ,
R ¹ and R ² together represent a cyclopentane, cyclohexane, cycloheptane, cyclooctane ring fused to the thiophene ring,
R ³ in the 3-position of the thiophene ring represents the residues CN, COR ⁶ , CONR ⁸ R ⁹ , COOR ⁷ ,
R ^{4 represents} hydrogen,
R ^{5 represents} C _1-6 alkyl, cycloalkyl having up to 6 C atoms, phenyl which is optionally substituted by halogen, in particular chlorine, nitro, methyl, i-propyl, methoxy, trifluoromethyl, and naphthyl,
R ^{7 represents} C _1-4 alkyl, in particular methyl, ethyl, n-, i-propyl, n-, t-butyl, and also phenyl,
R ^{8 represents} methyl,
R ^{9 represents} methyl.

In addition to the compounds mentioned in the examples, the following compounds may be mentioned:

The thienylamines or carbamates of the formula I are partially known. They can be analogous to known ones Produce process (DE-OS 21 22 636, US-P 43 17 915).

The active ingredients are used to promote performance in animals Promotion and acceleration of growth, milk and Wool production, as well as to improve feed utilization, the meat quality and the postponement of the Meat-fat ratio used in favor of meat. The active ingredients are used in livestock, breeding, animal and Hobby animals used.

The livestock and breeding animals include mammals such as B. Cattle, pigs, horses, sheep, goats, rabbits, Rabbits, fallow deer, fur animals such as mink, chinchilla, poultry such as B. chickens, turkeys, geese, ducks, pigeons, fish like e.g. B. carp, trout, salmon, eels, tench, pike, Reptiles such as B. snakes and crocodiles.

Ornamental and hobby animals include mammals and dogs and cats, birds like parrots, canaries, fish like Ornamental and aquarium fish e.g. B. Goldfish.

The active ingredients are independent of the sex of the animals during all growth and performance phases of the animals used. The active ingredients are preferred during intensive growth and performance phase. The intensive growth and performance phase lasts depending on Species from one month to 10 years.

The amount of active ingredients that the animals achieve the desired effect is administered, because of the  favorable properties of the active ingredients largely varied will. It is preferably about 0.001 to 50 mg / kg in particular 0.01 to 5 mg / kg body weight per day. The appropriate amount of the active ingredient and the appropriate duration of the Administration depend in particular on the type, age, the gender, the state of health and the type of Keeping and feeding the animals off and are by everyone Expert easily identified.

The active ingredients are used in the animals according to the usual methods administered. The mode of administration depends in particular on the type, behavior and state of health of animals.

The active substances can be administered once. The Active ingredients can also be used throughout or temporarily or continuously during part of the growth phase be administered. With continuous administration can apply one or more times a day at regular or irregular intervals.

It is administered orally or parenterally in for this suitable formulations or in pure form. Oral Formulations are powders, tablets, granules, doenche, Boli and feed, premixes for feed, formulations for administration via drinking water.

The oral formulations contain the active ingredient in concentrations from 0.01 ppm - 100%, preferably from 0.01 ppm - 1%.

Parenteral formulations are injections in the form of Solutions, emulsions and suspensions, as well as implants.  

The active ingredients can be used alone or in the formulations in a mixture with other active ingredients, mineral salts, Trace elements, vitamins, protein substances, dyes, Fats or flavorings are present.

The concentration of the active ingredients in the feed is usually about 0.01-500 ppm, preferably 0.1-50 ppm.

The active ingredients can be used as such or in the form of premixes or feed concentrates are added to the feed.

Example of the composition of a chick rearing feed containing the active ingredient according to the invention:
200 g wheat, 340 g maize, 361 g soybean meal, 60 g beef tallow, 15 g dicalcium phosphate, 10 g calcium carbonate, 4 g iodized table salt, 7.5 g vitamin-mineral mixture and 2.5 g active ingredient premix result after careful mixing 1 kg of feed.

One kg of feed mix contains:
600 IU vitamin A, 100 IU vitamin, D ₃ , 10 mg vitamin E, 1 mg vitamin K ₃ , 3 mg riboflavin, 2 mg pyridoxine, 20 mcg vitamin B ₁₂ , 5 mg calcium pantothenate, 30 mg nicotinic acid, 200 mg choline chloride, 200 mgMn So ₂ × H ₂ O, 140 mg ZN So ₄ × 7 H ₂ O, 100 mg Fe SO ₄ × 7 H ₂ O and 20 mg Cu So ₄ × 5 H ₂ O.

2.5 g of active ingredient premix contain z. B. 10 mg of active ingredient 1 g DL-methionine, rest soybean meal.  

Example of the composition of a pig rearing feed containing the active ingredient according to the invention:
630 g of feed grain meal (composed of 200 g corn, 150 g barley, 150 g oats and 130 g wheat meal), 80 g fish meal, 60 g soy meal, 60 g tapioca meal, 38 g brewer's yeast, 50 g vitamin-mineral mixture for pigs, 30 g linseed cake flour, 30 g corn gluten feed, 10 g soybean oil, 10 g sugar cane molasses and 2 g active ingredient premix (composition e.g. as with chick feed) result in 1 kg feed after careful mixing.

The specified feed mixtures are for rearing and fattening coordinated by preferably chicks or pigs, she can, however, in the same or a similar composition can also be used to feed other animals.  

Example A Rat feeding attempt

Female laboratory rats weighing 90-110 g, type SPF Wistar (Hagemann breed) are ad lib with standard rat food, with the desired amount of active ingredient is fed. Each experiment is fed with the identical batch carried out so that differences in the comparability of the composition of the feed Cannot affect results.

The rats receive water ad lib.

12 rats each form a test group and are with feed containing the desired amount of active ingredient offset is fed. A control group receives feed without active ingredient. The average body weight as well the variation in the body weights of the rats is in each test group the same, so that comparability the experimental groups are guaranteed among themselves.

During the 13-day trial, weight gain and Determined feed consumption.

It shows the results shown in the table receive:  

Table 1: Rat feeding experiment

Manufacturing examples example 1

2-aminomethoxycarbonyl-3-carbethoxy-4-ethyl-5-methylthiophene

5 g (0.021 mol) of 3-carbethoxy-4-ethyl-2-isocyanato-5-methylthiophene were added to 40 ml of dry methanol and heated under reflux for one hour. Excess methanol was then distilled off in vacuo and the residue was distilled in the bulb tube on the oil pump.
Yield 3.7 g (65%), boiling point 156 ° C (1 Pa), IR: 3300, 1730, 1660.

Example 2

2-methoxycarbonylamino-3-ethoxycarbonyl-4,5-trimethylene-thiophene  

6.33 g (30 mmol) of 2-amino-3-ethoxycarbonyl-4,5-trimethylene-thiophene and 2.37 g (30 mmol) of pyridine are dissolved in 50 ml of dry chloroform with a solution of 3.1 g (33 mmol ) Methyl chloroformate in 20 ml of dry chloroform. After one hour, the mixture is washed 3 × with 30 ml of water, 1 × with 30 ml of 10% hydrochloric acid and 2 × with 30 ml of water each time, dried over Na ₂ SO ₄ , evaporated and recrystallized from ethanol.
Beige crystals, mp 102 ° C, yield 6 g (75%).

Example 3

2-phenoxycarbonylamino-3-carbethoxy-4-ethyl-5-methylthiophene

2.2 g (0.023 mol) of phenol are added to a solution of 5 g (0.021 mol) of 3-carbethoxy-2-isocyanato-4-ethyl-5-methylthiophene in 40 ml of dry toluene, and the whole is increased to 60 for one hour ° C warmed. It is then cooled and the organic phase is washed in succession with 100 ml of 5% H ₂ SO ₄ , water and saturated NaHCO ₃ solution. The toluene is distilled off in vacuo and the residue is recrystallized from dilute aqueous ethanol. Yield: 4.2 g (60% of theory), melting point: 103 ° C.

The following compounds were obtained analogously:

Claims (7)

1. Use of substituted thienylamines of the formula I. in which
A stands for the rest Ia X represents O or S,
R ^{1 represents} hydrogen, halogen, nitro, CN, alkoxy, alkylthio, haloalkoxy, haloalkylthio, optionally substituted radicals from the group alkyl, acyl, aroyl, aryl,
R ^{2 represents} hydrogen, halogen, nitro, CN, alkoxy, alkylthio, haloalkoxy, haloalkylthio, optionally substituted radicals from the group acyl, aroyl, alkyl, aryl,
R ¹ and R ² together with the adjacent C atoms represent an optionally substituted or unsaturated carbocyclic or heterocyclic ring which can optionally carry a carbonyl function,
R ^{3 represents} the residues CN, COR ⁶ , COOR ⁷ , CONR ⁸ R ⁹ ,
R ^{4 represents} hydrogen or alkyl,
R ^{5 represents} optionally substituted alkyl, cycloalkyl, alkenyl, optionally substituted aryl,
R ^{6 represents} optionally substituted alkyl or optionally substituted aryl,
R ^{7 represents} hydrogen, optionally substituted alkyl, cycloalkyl, alkenyl, optionally substituted aryl,
R ^{8 represents} alkyl or cycloalkyl,
R ^{9 represents} optionally substituted alkyl,
as a performance enhancer for animals. 2. Means marked for performance promotion of animals by a content of substituted Thienylamines of the formula I according to claim 1.   3. Animal feed, drinking water for animals, additives for animal feed and drinking water for animals characterized by a content of substituted thienylamines Formula I according to claim 1. 4. Use of substituted thienylamines Formula I according to claim 1 for the promotion of performance Animals. 5. Process for the production of means to promote performance of animals, characterized in that one substituted thienylamines of the formula I according to Claim 1 with extenders and / or diluents mixed. 6. Process for the production of animal feed, drinking water for animals or additives for animal feed and drinking water for animals, characterized in that one substitutes Thienylamines of the formula I according to claim 1 with Feed or drinking water and if necessary mixed with other auxiliaries. 7. 2-aminomethoxycarbonyl-3-carboethoxy-4-ethyl-5-methyl thiopia.